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International consensus statement on rhinosinusitis

well as a continuum of pathophysiology between CRSwNP and CRSsNP patients. 41–45 Aided by advances in molec ular and statistical techniques, several research groups have worked toward defining endotypes, or biological inflammatory subtypes of CRS, based on mucus and tis sue biomarkers. 46–50 This effort has been further accel erated by the development of several novel therapeutic monoclonal antibodies targeting potential inflammatory mediators of CRS, 56–58 as there is a need to determine which patients will benefit from these treatments. 14 Over all, endotype research in CRS has drawn inspiration from a similar effort in the management of asthma, 51 whichhas led to improved understanding of the underlying patho physiology and better outcomes in treatment refractory patients. 52,53 Along with the advances in understanding endotypes, some of the nomenclature around inflammatory patterns has evolved. Th1, Th2, and Th17 inflammatory patterns are now often referred to as Type 1, Type 2, and Type 3 patterns, respectively (Figure I-2). Much of the evidence reviewed throughout this ICAR-RS-2021 document uses the previ ous terminology while some includes the newer classifica tion pattern. Inasmuch as this nomenclature is in evolu tion, both are used throughout the document. A number of studies have identified putative endo types in phenotypically heterogenous CRS populations using unsupervised cluster analysis of tissue and mucus biomarkers. The first study defining potential endotypes of CRS was published in 2016 by Tomassen et al. 49 The study assayed inflammatory markers in 173 European patients and reported 10 distinct CRS clusters or endotypes using 11 tissue biomarkers. Six clusters were noted to have high tissue levels of type 2 inflammatory markers (Th2). These 6 clusters were IL-5 positive, with a “moderate” IL-5 group characterized by mixed CRSsNP/CRSwNP with asthma phenotype, and a “high” IL-5 group predominantly con sisting of patients with nasal polyposis and asthma that also had concomitant high levels of S. aureus specific IgE. Within the 4 low Th2 clusters, IL-5 was negative, and most groups were CRSsNP without asthma, with 1 clus ter demonstrating a mixed phenotype and high IL-17 lev els. Overall, about 56% of patients clustered into a mod erate/high Th2 endotype, including a majority of patients with CRSwNP. Divekar et al. 47 utilized a commercial immunoassay of 41 inflammatory markers and MPO to examine sinonasal tissue from 26 patients. The study identified 3 inflamma tory endotypes: a Th1/Th17 group, a Th2 dominant group,

and a growth factor dominant group. In a larger cohort of 90 CRS patients, Turner et al. 46 identified 6 disease clus ters using a panel of 18 soluble mucus cytokines. This study offered a less invasive method of endotyping than studies using tissue, and the authors proposed that mucus could be used for longitudinal analysis. 157 The majority of CRS patients had elevation of Th2 markers, but only a limited subset had a Th2 dominant profile. Two clusters were noted to have a relatively low inflammatory burden comparable with controls, with a final group demonstrat ing a high level of IL-1b and more neutrophilic disease. Another study conducted by Liao et al. 48 in 246 Chinese patients identified 7 unique clusters using tissue inflam matory biomarkers as well as clinical variables. In con trast to studies in Western countries, only 13% of Chinese patients with CRSwNP had a type 2 dominant inflamma tory signature, and neutrophilic inflammation groups were associated with a higher percentage of “difficult-to-treat” patients. A similarly subdued pattern of type 2 inflamma tion relative to studies in the U.S. and Europe was noted in an endotyping study of 93 CRS patients in New Zealand. 50 Notably, this study also incorporated bacterial community data to assess variances between endotypes, but did not find any significant differences. Despite these promising initial findings, endotypic clas sifications are still in their infancy. Although there is a lack of consensus on the use of biomarkers for endotyping, it is evident that Th1, Th2, and Th3 markers (also referred to as type 1, 2, and 17 immune reactions) should be included. Additionally, there is increasing evidence that differentiat ing type 2 vs non-type 2 endotypes is clinically meaningful, as type 2 immune reactions are associated with asthma, 49 an increased risk of recurrence after surgery, 55 and are the basis for the use of innovative type 2 biologics. 56–60 There appear to be substantial global variations in the dis tribution of CRS endotypes as well, likely driven by unde fined environmental factors which merit further study. 54 Finally, treatment stratifications based on endotypes have been proposed, but prospective data associating endo types with long-term disease outcomes remain limited. 48,59 As work in this field evolves, however, it is likely that future evidence-based recommendation statements will increasingly utilize classification schemes based on endotypes.

CRS Endotyping Aggregate Grade of Evidence: C (Level 4: 5 studies; Table V-3).